The overall goal of this application is to investigate the role of bone marrow-derived stem cells in the development and progression of gastric cancer. Epithelial cancers are believed to originate from transformation of a tissue stem cell, but a second possible source of cancer stem cells is the bone marrow derived cell (BMDC). Epithelial cancers often arise in the setting of tissue loss and inflammation, and are preceded by hyperproliferation and metaplasia. Our group utilized has developed the Helicobacter mouse model of gastric cancer to address the origins of epithelial cancers. These studies from our laboratory suggest that chronic infection of C57BL/6 mice with Helicobacter, a known carcinogen, leads to chronic inflammation and repopulation of the stomach with BMDCs that then progress to metaplasia, dysplasia to intraepithelial cancer [Science 2004;306:1568-1571]. These findings from our laboratory suggest that epithelial cancers may originate from marrow-derived sources and have broad implications for the multistep model of cancer progression. We propose to use this model system to investigate further the biology of bone marrow-derived stem cells in cancer. Our aims in this proposal will address the following questions: (1) What is the origin of the cancer stem cells and is there any correlation with number of circulating cells? (2) Are bone marrow stem cells inherently more susceptible to malignant progression than tissue stem cells, and can they differentiate into mature gastric cells? (3) Do IL-1 beta and other cytokines activate the immune system to result in cancer initiation? (4) Is bacterial overgrowth, a consequence of achlorhydria, necessary for progression of BMDCs to dysplasia and gastric cancer? (5) Do inherited (e.g. p53) genetic mutations in the bone marrow stem cell population lead to cancer irreversibility in the setting of histologic dysplasia? These collaborative studies between investigators at Columbia University and MIT will provide new insights into mechanisms of cancer initiation and progression.